The present invention is directed to a method of inhibiting Cathepsin B, a lysosome cysteine protease.
Cysteine proteases such as Cathepsins B, H, K, L, O and S, represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increased expression or enhanced activation, however, has pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, periodontal disease, and metachromatic leukodystrophy. For example, increased Cathepsin B levels and redistribution of the enzyme are found in tumors, thus demonstrating a role for the enzyme in tumor invasion and metastasis. In addition, aberrant Cathepsin B activity is implicated in such disease states as Alzheimer's Disease, arthritis, inflammatory diseases such as chronic and acute pancreatitis, inflammatory airway disease, and bone and joint disorders, including osteoporosis, osteoarthritis, rheumatoid arthritis, psoriasis, and other autoimmune disorders.
Cathepsin B is also associated with fibrotic disease, including HCV-associated liver fibrosis, all types of steatosis (including non-alcoholic steatohepatitis) and alcohol-associated steatohepatitis, non-alcoholic fatty liver disease, forms of pulmonary fibrosis including idiopathic pulmonary fibrosis, pathological diagnosis of interstitial pneumonia following lung biopsy, renal fibrosis, cardiac fibrosis, retinal angiogenesis and fibrosis/gliosis in the eye, scleroderma, and systemic sclerosis.
In view of the number of diseases or conditions related to the normal activity or the increased expression of Cathepsin B, compounds that are capable of inhibiting enzymatic protease activity or expression would accordingly be useful.
Compounds that were disclosed in U.S. Patent Application Publication No. 2007/0054864, filed Jun. 28, 2006, and U.S. Patent Application Ser. No. 60/878,544, the complete disclosures of which are hereby incorporated by reference, were shown to have the ability to inhibit HCV replication, and are therefore useful in treating hepatitis C.
Surprisingly, we have discovered that these compounds, and analogs of these compounds, are also useful as inhibitors of the cysteine protease Cathepsin B. Accordingly, such compounds are useful as therapeutic agents for the treatment of tumor invasion, metastasis, Alzheimer's Disease, arthritis, inflammatory diseases such as chronic and acute pancreatitis, inflammatory airway disease, and bone and joint disorders, including osteoporosis, osteoarthritis, rheumatoid arthritis, psoriasis, and other autoimmune disorders, liver fibrosis, including liver fibrosis associated with HCV, all types of steatosis (including non-alcoholic steatohepatitis) and alcohol-associated steatohepatitis, non-alcoholic fatty liver disease, forms of pulmonary fibrosis including idiopathic pulmonary fibrosis, pathological diagnosis of interstitial pneumonia following lung biopsy, renal fibrosis, cardiac fibrosis, retinal angiogenesis and fibrosis/gliosis in the eye, scleroderma, and systemic sclerosis.
It is clear that the ability of a single compound to both inhibit HCV replication and Cathepsin B in a mammal is an advantageous property, in that viruses, including chronic HCV infection, promote inflammation and liver injury. As a direct result of this inflammation and liver injury HCV can lead to progressive liver fibrosis, with a number of chronic HCV-infected patients eventually developing cirrhosis. A majority of the serious complications associated with chronic HCV infection results from the development of liver cirrhosis. The treatment of subjects with such a compound, with the ability to inhibit HCV replication and directly reduce fibrotic disease, would improve clinical outcomes.